1. Field of the Invention
The present invention relates generally to methods and devices for administering biologically-active substances for delivery to desired in vivo locations, as might be particularly useful in treating blood vessels or grafts following angioplasty procedures.
While systemic administration of drugs or other biologically-active substances is satisfactory for many medical treatments, many other treatments can be facilitated and/or improved with local drug delivery or administration to selected portions of internal body tissues. Localized drug administration is particularly advantageous where drug retention in the treated locus is required for an effective period of time without appreciably affecting other body tissues. Strictly by way of example, drug delivery to a specific locus can be desired in the treatment of cancerous tumors or the like. In the treatment of such tumors, often an objective is to administer the cancer drug so that it localizes, as much as possible, in the tumor itself in order to limit systemic toxicity.
Another exemplary treatment for which localized drug delivery is desirous involves prevention of vessel renarrowing, or restenosis, following percutaneous revascularization techniques, such as percutaneous transluminal angioplasty (PTA). Although PTA provides an alternative to bypass surgery for relieving stenosis of obstructive atherosclerotic blood vessels, the long-term success of the angioplasty is often compromised by the onset of restenosis thereby requiring reintervention. In the PTA procedure, an inflatable balloon disposed at the distal end of a catheter is positioned in the region of a stenosis. The balloon is inflated under fluid pressure to reconfigure the narrowed lumen and thereafter permit increased blood flow through the affected artery. It is not unusual that inflation-deflation cycles will be repeated several times where the narrowing is severe. This mechanical violence to the arterial wall may produce the desired opening of the artery, but in delayed consequence the procedure is followed by an estimated 25%-50% incidence of restenosis, typically within 6 months to 2 years of the procedure (depending on the location), at or near the injured site.
Studies have suggested a number of conditions which lead to vessel restenosis, including remodeling and intimal hyperplasia. These studies have indicated that vessel injury, such as endothelial denudation, injury to the vascular wall, and rupture of the vasa vasorum, can result as an unwanted consequence to an angioplasty thereby making the treated site susceptible to restenosis. Upon injury, the ensuing deposition of platelets, in connection with the vessel's healing mechanism, signals smooth muscle cell proliferation within the arterial wall. The deposition of platelets may lead to acute thrombosis in some circumstances. More significantly, the proliferation of smooth muscle cells is a process which frequently continues unabated and has therefore been widely implicated as a prominent factor in the resulting restenosis. No pharmacologic or mechanical intervention has heretofore proven sufficiently effective in preventing restenosis following angioplasties.
2. Description of the Prior Art
The prior art has proposed various techniques that attempt to prevent restenosis following an angioplasty. A mechanical strategy has involved the use of stents with the hope that the radial expansile force that stents exert would restore luminal integrity and preserve maximum vessel diameter. In use, however, whereas stents have demonstrated some measure of success in limiting abrupt reclosure and remodeling following vascular intervention, stents have been quite unsuccessful in preventing the more progressive condition of restenosis. Because of their rigid nature, stents actually can induce vessel injury and hence intrastent thrombosis and restenosis.
Other approaches have focused on the administration of smooth muscle cell growth regulators. Most of these approaches have attempted to provide localized delivery inasmuch as systemic dosing through intravenous infusion or oral ingestion is inadequate because of the risk of hemorrhage and other complications. For example, Rogers et al., Circulation, 88:1215-1221 (1993), discuss the use of heparin, an inhibitor of vascular smooth muscle cell proliferation, as a way to limit neointimal hyperplasia following arterial injury. The Rogers et al. article emphasizes that more chronic and severe vessel damage demands prolonged administration of antiproliferative agents in order to attenuate the possibility of hyperplasia and restenosis. In practice, however, previous attempts to deliver antiproliferative agents have not met with success in achieving prolonged prevention of restenosis, as discussed in detail below.
Among prior art delivery approaches is the use of catheter systems to treat the primarily local vascular response to injury. In one catheter system, an inner balloon is inflated to firmly place an outer balloon of the catheter in direct contact with the vessel wall. The outer balloon of the catheter, which is in contact with the vessel, is defined by a drug transport wall which is constructed of a material that is selectively permeable and, thus, permits selective transport of a drug therethrough. For example, this drug transport wall is constructed of perforated, permeable, microporous or semipermeable material through which the drug is intended to selectively pass. Another similar catheter system contains two separated expansile portions which, when pressurized, form a space therebetween. Blood may then be removed from the space and a biologically active substance may be placed therein to come into direct contact with the vessel wall. Another catheter system for drug delivery is described in U.S. Pat. No. 5,171,217 to March et al. According to March et al., a drug carried by microparticles of a physiologically-compatible, biodegradable polymer, is intramurally injected under directed pressure into the wall of a body vessel in the region of the affected site.
These catheter delivery systems are unsatisfactory because, among other things, the catheter must reside within the blood vessel for a significant length of time, causing discomfort and inconvenience to the patient. Further, prolonged instrumentation, as is necessitated by many intraluminal devices, also increases the risk of thrombosis. Additionally, even after a significant length of time, insufficient amounts of the drug typically enter the target cells to achieve the desired result. Indeed, a significant problem with delivery of drugs via catheter systems is that the drug is diluted and carried away in the turbulent and high velocity blood stream. Accordingly, high pressure transmural perfusions from intravascular catheters merely provide transient luminal drug delivery inasmuch as lasting drug levels in the vessel have not been demonstrated. Significantly, the perfusion catheter itself produces local injury and necrosis to the endothelium and adjacent tissue, presumably as a result of the high pressures used to instill drugs, and, as such, actually induces restenosis while delivering a drug for the purpose of preventing restenosis. These procedures also add to the time, cost, complexity, pain and morbidity of, for example, post-angioplasty procedures and do not result in adequate dosage of the active substance to target cells. There is also a significant risk that systemic levels of drug will be achieved when perfusion catheters are utilized for drug delivery.
Other approaches for drug delivery have attempted to combine the mechanical support offered by stents with drug delivery. For example, Rogers and Edelman, Journal of Interventional Cardiology, 5:195-201 (1992), describe the use of endovascular stents containing drug-eluting coatings. This drug delivery system was devised to overcome intrastent thrombosis, a condition which plagued previous stent placement procedures. However, drug-eluting coatings do not permit a sustained reduction in smooth muscle cell proliferation. In this regard, these coated stents release most of their drug within the first hours of deployment and do not provide penetrating delivery to the vessel wall for a prolonged period of time. Another approach is found in Slepian, Contemporary Interventional Techniques, 12:715-737 (1994), which describes time-limited endoluminal wall support in the form of polymeric endoluminal paving. In this system, tubes or sheets of biodegradable drug delivery polymers are transported intraluminally via a catheter system and locally thermoformed, yielding supportive, thin polymeric endoluminal liner layers. This type of drug delivery is also unsatisfactory because it requires placement using a catheter, does not yield prolonged drug delivery, and is associated with a significant increase in the time, cost, complexity, pain and morbidity of related procedures.
Similarly, Hill-West et al., Proc. Natl. Acad. Sci., 91:5967-5971 (1994), describe the application of hydrogel barriers that are provided on the inner surface of injured arteries. According to Hill-West et al., the barrier can be used for the controlled release of macromolecular drugs. As the gel loosens by degradation, the drug is slowly released. This approach likewise suffers from an inadequate residence time because much of the drug that is delivered dissolves downstream away from the desired localized site. The proposal identified by Hill-West et al. is also greatly restrained inasmuch as drug delivery is not possible after the gel dries.
Yet another type of localized drug delivery is described in Edelman et al., Proc. Natl. Acad. Sci., 87:3773-3777 (1990). Edelman et al. discuss site-specific therapy following vascular interventions in which ethylene/vinyl acetate copolymer matrix is utilized to permit heparin delivery over time. In practice, however, the approach described by Edelman et al. is ill-suited for treating restenosis in vivo because the matrices must be surgically deployed. Because angioplasties and other intravascular interventions demonstrate value by producing desired results while obviating the need for open operation, the performance of an operation to improve the results of an intravascular intervention negates the clinical value of that interventional procedure.
Despite the availability of the foregoing prior art approaches, it will be appreciated that there still exists a need in the art for a method of localized drug delivery which does not require a surgical procedure and which delivers a drug in a timed-release fashion wherein the drug delivery is sustained in its desired localized site. For example, there exists a specific need for localized drug delivery to blood vessels or grafts in order to inhibit the onset of restenosis following angioplasty or other intravascular interventions in which the drug delivery is released over time and wherein the drug does not get carried away in the blood stream or get undesirably diluted therein. There also exists a need for drug delivery to blood vessels or grafts in which a vessel's lumen and endothelium are not subject to injury and in which a surgical procedure is not required.